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Extensively drug-resistant tuberculosis: new strains, new challenges

Expert. Rev. Anti Infect. Ther. 6(5), 713­724 (2008)

Ritu Banerjee, Gisela F Schecter, Jennifer Flood and Travis C Porco

Author for correspondence Division of Infectious Disease, Department of Pediatrics, University of California, San Francisco, 500 Parnassus Avenue, MU407E, San Francisco, CA 94143-0136, USA Tel.: +1 415 476 0136 Fax: +1 415 476 1343 [email protected]

Extensively drug-resistant (XDR)-TB, defined as TB with resistance to at least isoniazid, rifampin, a fluoroquinolone and either amikacin, kanamycin or capreomycin, is a stark setback for global TB control. Overburdened public-health systems with inadequate resources for case detection and management and high HIV coinfection rates in many regions have contributed to the emergence of XDR-TB. Patients with XDR-TB have poor outcomes, prolonged infectious periods and limited treatment options. To prevent an epidemic of untreatable XDR-TB, improvements in XDR-TB surveillance, increased laboratory capacity for rapid detection of drug-resistant strains, better infection control and the development of new therapeutics are urgently needed.

Keywords : drug-susceptibility testing · extensively drug-resistant tuberculosis · multidrug-resistant tuberculosis · second-line drug · tuberculosis


Extensively drug-resistant (XDR)-TB is a global reality that threatens TB control. XDR-TB is defined as TB with resistance to at least isoniazid (INH), rifampin, any fluoroquinolone (FQ) and one of three second-line injectable drugs (amikacin, kanamycin or capreomycin) [1] . XDR-TB is resistant to all drugs with effective bactericidal activity against Mycobacterium tuberculosis, making treatment of XDR-TB patients more challenging and less successful than that of patients with other types of TB. XDR-TB is a subset of multidrug-resistant (MDR)-TB, which is defined as being resistant to at least INH and rifampin. Although XDR-TB strains have been recognized for over a decade, surveillance data on the worldwide prevalence of XDR-TB were only first published in March 2006 [2] . Between 2000 and 2004, XDR-TB was found in 17 countries. Data from most African and Asian countries were limited. Of 17,690 TB isolates, 20% were MDR-TB and 2% were XDR-TB, using an earlier definition of XDR-TB (resistance to INH, rifampin and at least three of the six classes of second-line drugs [SLDs]) that has since been revised. These isolates were sampled from supranational reference laboratories, where MDR-TB isolates were probably over-represented. Nevertheless,


the proportion of XDR-TB among MDR-TB isolates was astoundingly high in some nations: 15% in Latvia and 19% in Korea [2] . More recent surveillance data from the WHO indicate that XDR-TB is now found in 45 countries (Figure 1) [3] . Among approximately 4000 MDR-TB isolates collected throughout the world and tested for susceptibility to SLDs, 7% were XDR-TB. The proportion of XDR isolates among MDR isolates varied among nations, from 0 to 30%, with Japan, the Republic of Korea and countries of the former Soviet Union reporting the highest proportions. The nations with the greatest absolute number of reported XDR-TB cases include countries of the former Soviet Union and South Africa [3] . In the USA, between 1993 and 2006, 49 patients (3% of the evaluated MDR-TB cases) have been reported with XDR-TB, mostly in areas with high TB morbidity and large immigrant populations, such as New York City and California [4] . In California alone, 18 XDR-TB cases, comprising nearly 4% of the evaluated MDR cases, were reported between 1993 and 2006 [5] . In addition, there are increasing surveillance data regarding MDR-TB isolates that are resistant to a FQ or an injectable agent, but not both (preXDR isolates). These strains are essentially one mutation away from becoming XDR. Among evaluated MDR isolates, pre-XDR prevalence

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© 2008 Expert Reviews Ltd



Banerjee, Schecter, Flood & Porco

Argentina Armenia Australia Azerbaijan Bangladesh Botswana Brazil Canada Chile China Hong Kong SAR Czech Republic Ecuador Estonia France Georgia Germany India Ireland Islamic Rep. of Iran Israel Italy Japan Latvia Lesotho Lithuania

Mexico Moldova Mozambique Namibia The Netherlands Nepal Norway Peru Phillippines Poland Portugal Republic of Korea Romania Russian Federation Slovenia South Africa Spain Swaziland Sweden Thailand UK Ukraine USA Vietnam

Figure 1. Extensively drug-resistant (XDR)-TB in the world. Countries with confirmed XDR-TB cases as of June 2008 are shown

with red circles and are listed on the left. Modified with permission from [202] .

was found to be 14% in a South African convenience sample [6] , 18% in California [5] , 25% in Uzbekistan [7] and 42% in Russia [8] . Although our understanding of the magnitude and distribution of XDR-TB is increasing, currently available reports of XDR-TB prevalence are underestimated because drug-susceptibility testing (DST) is incomplete and surveillance data are lacking from many nations. In many low-income, high-TBburden countries, poor laboratory capacity prevents culture and DST of M. tuberculosis. Even in high-income nations (that primarily contributed surveillance data for the WHO report on anti-TB drug resistance) [3] , a large proportion of MDR cases did not have SLD-susceptibility testing and could not be assessed for XDR-TB.

Emergence & spread of XDR-TB

Within a population of M. tuberculosis organisms, mutations conferring resistance to anti-TB drugs occur spontaneously and are propagated by subinhibitory antibiotic concentrations. Acquired drug resistance occurs when drug-sensitive TB strains become drug resistant during treatment, and amplified drug resistance occurs when drug-resistant M. tuberculosis strains become resistant to additional drugs during retreatment. Finally, primary drug resistance occurs when drug-resistant strains are transmitted to new TB cases. All forms of drug resistance have contributed to the emergence and spread of XDR-TB.


Acquired and amplified drug resistance occur most often in patients on poor drug regimens or those with adherence gaps, malabsorption (more common among HIV-infected patients) or limited antibiotic penetration into granulomas, empyemas or extensive cavities [9,10] . In many settings, overburdened publichealth systems have insufficient resources for laboratory diagnosis, DST or case management, and lack access to costly secondline medicines. This results in delayed MDR-TB diagnosis and treatment, inadequate treatment and poor adherence during therapy. There is an increased risk of noncompliance and treatment interruptions during therapy of MDR-TB, given the long duration of treatment and the use of drugs that have frequent side effects. Loss of follow-up because patients live far from clinics or hospitals is also a major reason for adherence gaps [11] . In some areas, increased and unsupervised use of SLDs for the treatment of MDR-TB and other infections has contributed to the development of XDR-TB strains. Areas with long histories of unregulated SLD use (e.g., countries of the former Soviet Union and Korea) now have the highest proportion of XDR-TB among MDR-TB cases in the world [3,12,13] . By contrast, in areas such as Hong Kong, which have strict regulation of SLD use and well-functioning TB-control programs, amplification of drug resistance has been low [14] . A recent analysis describes the evolution of XDR strains from MDR strains in South Africa via amplification of drug resistance. Pillay et al. tracked the drug-resistance patterns of isolates of the F15/LAM4/KZN strain from Kwazulu-Natal (South Africa)

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Extensively drug-resistant TB: new strains, new challenges


between 1994 and 2005. They found that resistance to as many as seven drugs developed in this strain in slightly over a decade [15] . They hypothesize that development of XDR-TB was promoted by lack of DST, the practice of adding a single agent (usually streptomycin) to failing regimens, and standardized treatment of all MDR-TB patients, even those whose M. tuberculosis isolates had additional SLD resistance. These patients were essentially treated with only one or two active drugs, leading to treatment failure and amplification of drug resistance. In addition, primary drug resistance or transmission of XDR-TB strains has occurred in a number of settings to date. Nosocomial spread of XDR-TB is strongly suggested by an XDR-TB outbreak in Kwazulu-Natal [16] , where high HIV prevalence and congregate hospital wards without adequate ventilation or capacity for isolation facilitated spread. In this setting, at least 17 individuals, initially infected with non-XDR-TB strains, became superinfected with XDR-TB strains during hospitalization [11] . In Iran, genotypic analysis has shown community transmission of XDR strains in two clusters, one involving a single family and the other a group of close contacts [17] . In Norway, a single XDR patient lost to follow-up resulted in XDR-TB transmission to 14 other patients over a decade [18] . In California, USA, two cases of XDR transmission occurred among household contacts [5] . How widespread a drug-resistant strain becomes is a result of a complex interplay between transmissibility and relative fitness of the strain [19,20] , host immunity (i.e., HIV prevalence) and TB-control practices that impact treatment and cure rates. Blower and colleagues presented a mechanism of MDR epidemiology, including transmission, acquired drug resistance and amplification of drug resistance [21] , that may provide insight into XDR-TB; if MDR-case-detection and treatment rates increase without similar increases in cure rates, a substantial rise in the number of XDR-TB cases can be expected [22] . This would be due to acquisition of resistance to more classes of drugs by MDR strains, as well as transmission of existing XDR strains. Recently, a detailed transmission model of XDR-TB was used to estimate the effect of various interventions on XDR-TB incidence in Tugela Ferry, South Africa [23] . This model was calibrated using longitudinal community-based and in-patient data, and was used to estimate that, under current conditions, 1300 new XDR-TB cases would occur by 2012, more than half of which would be acquired through nosocomial transmission. However, using a combination of low-cost infection-control strategies, such as wearing masks and reducing hospital length of stay, and more expensive measures, such as use of rapid drug-susceptibility assays, improved ventilation and isolation facilities, half of the estimated new XDR-TB cases could be prevented. The modeling results strongly indicate that such measures should be instituted urgently [24] . The results of this model also suggest that eliminating the threat of XDR-TB will require additional community-based efforts.

Clinical/demographic characteristics

Several recent studies from diverse regions of the world have described clinical and demographic factors associated with XDR-TB. XDR-TB patients have high rates of treatment failure

and mortality, especially when coinfected with HIV in resourcelimited settings. In 2006, a study of a lethal XDR-TB outbreak in Kwazulu-Natal, South Africa, catapulted XDR-TB to international attention [16] . In a single hospital in this rural province, 53 patients had XDR-TB; almost all patients were coinfected with HIV and all but one died. The median time from sputum collection to death was 16 days. It is likely that these patients had recently acquired XDR-TB, perhaps through nosocomial transmission, since 85% of the strains showed genetic clustering and most patients gave no prior history of TB but did report recent hospitalization [16] . HIV-uninfected XDR-TB patients also have worse outcomes than patients with other forms of TB, even in settings with welldeveloped healthcare systems. In a retrospective study from Italy and Germany, XDR-TB cases had a five-fold increase in the risk of death, required longer hospitalization and longer treatment than did MDR cases [25] . In a subsequent study, these authors combined cases identified between 1999 and 2006 in Italy, Germany, Estonia and the Russian Federation to obtain a total of 361 MDR-TB cases and 64 XDR-TB cases. They found that the relative risk of treatment failure or death for XDR-TB patients was 1.58 compared with MDR-TB cases resistant to all first-line drugs and 2.6 compared with MDR-TB cases sensitive to at least one first-line drug [26] . The mortality of XDR-TB patients was 25%, while that of MDR-TB patients resistant to all first-line drugs was 15%. Poor outcomes were also observed in HIV-negative XDR-TB patients in Korea. From 1996 to 2005, among 43 XDR-TB patients, 44% had treatment failure and 14% died. By contrast, among non-XDR patients, 27% had treatment failure and 7% died. XDR patients had worse outcomes despite the fact that they were exposed to more anti-TB drugs for a longer duration. Multivariate analysis revealed that XDR-TB patients had a 4.5-times higher risk of treatment failure than did non-XDR-TB patients [27] . In the USA, a high-income, low-TB-burden nation with generally effective TB-control programs, XDR-TB outcomes have also been poor. Nationally, of 41 patients with XDR-TB and known treatment outcomes, nearly a third died, the majority of whom were HIV positive [4] . In California, USA, among 12 patients with XDR-TB and known outcomes between 1993 and 2004, five died [5] . In both US studies, there were significant improvements in mortality in the later half of the study period, perhaps due to increased use of directly observed therapy (DOT) and experience gained in MDR-TB treatment [4,5] . Of note, in US national data since 2000, there was a decrease in the proportion of XDR-TB patients with HIV coinfection [4] . Pre-XDR-TB patients also appear to have worse outcomes than MDR-TB patients. A study of MDR-TB patients from four different European countries found that FQ-resistant MDR-TB cases had higher mortality and more treatment failure than FQ-sensitive MDR-TB cases [26,28] . In a recent ana lysis, capreomycin resistance was found to be an independent predictor of treatment failure among MDR patients [29] . In Korea, MDR-TB patients that had kanamycin-resistant isolates were nearly four-times more likely than those with kanamycin-susceptible isolates to have positive sputum cultures 6 months after therapy initiation [13] .



Banerjee, Schecter, Flood & Porco

Demographic characteristics of XDR-TB patients differ in lowTB-burden nations and in low-income nations with high HIV and TB prevalence. The vast majority of XDR patients studied in Europe, the USA and Korea were HIV negative and had a history of prior TB treatment. In these regions, prior TB treatment was elicited in 75 [26] , 100 [13] and 50% [5] of XDR-TB patients, respectively. In a prospective study of MDR patients in Korea, cumulative previous treatment duration was associated with XDR-TB [13] . In stark contrast, in South Africa, most XDR-TB patients were coinfected with HIV and did not report prior TB treatment [16] . In Western Europe and the USA, the majority of XDR cases, such as MDR cases, occur in foreign-born individuals arriving from nations with high TB incidences [5,25,30,31] . While US national surveillance data indicate that immigrants from Asia account for the majority of XDR cases [4] , in California most

XDR-TB cases occur in individuals born in Mexico [5] . In studies from California and Europe, there were no significant differences observed in age, radiographic findings or occurrence of extrapulmonary TB disease observed between XDR and MDR cases [5,25] . By contrast, in a study of HIV-negative patients in Korea, XDR-TB patients had more bilateral cavitary lung disease than did non-XDR-TB patients [27] . Many of the above studies also report the alarming observation that XDR-TB patients have protracted infectious periods. This is likely due to inadequate suppression of organisms that are drug resistant and are present in high concentrations in patients with extensive and advanced disease. In most studies, XDR-TB patients were alive for months, often with positive sputum smears and cultures and cavitary pulmonary disease. Among XDR-TB patients, cavitary lung disease was seen in 86% of patients in Korea [27] and in 30% of patients in California [5] . In US studies, sputum smears were positive in half Table 1. Classes of anti-TB drugs and genes mutated in to two-thirds of XDR-TB patients [4,5] . drug resistance. Overall, less than half of XDR-TB patients converted sputum cultures from positive Anti-TB drug Genes mutated in resistance to negative. In a Korean study, sputum First-line drugs cultures remained positive 6 months after Isoniazid katG, inhA, ahpC, oxyR, kasA, furA, ndh initiating TB therapy in 81% of XDR-TB patients compared with 21% of MDR-TB Rifampin rpoB patients [13] . Sputum culture conversion Ethambutol embCAB was documented in only half of XDR-TB Pyrazinamide pncA patients in California [5] and a third of Streptomycin rrs, rpsL, gidB patients in Europe [25] . In California, in cases where sputum cultures did become Second-line drugs negative, time to culture conversion was Fluoroquinolones gyrA, gyrB prolonged, with a median time of 195 days Injectables: for XDR-TB compared with 99 days for · Kanamycin and amikacin rrs MDR-TB and 60 days for other TB iso· Capreomycin rrs, tlyA lates [5] . Similarly, in a European cohort, Streptomycin rrs, rpsL, gidB XDR patients had longer times for sputum Cycloserine alrA, ddl* culture conversion compared with MDR patients [25] . Ethionamide inhA, etaA/ethA

Para-aminosalicylic acid Unknown

Third-line drugs

Amoxicillin­clavulanate Imipenem Clarithromycin Linezolid Clofazimine

Resistance determinants

Agents in clinical development

TMC207 (diarylquinoline) OPC67683 (nitroimidazole) PA824 (nitroimidazole) LL3858 (pyrrole) SQ109 (diamine)


Has been shown in Mycobacterium smegmatis.

Antibiotic resistance in M. tuberculosis develops primarily through mutations in chromosomal genes. M. tuberculosis lacks plasmids, has a low recombination rate and contains a unique, impermeable cell wall that prevents horizontal transfer of resistance genes [32,33] . The genes mediating resistance to many first- and secondline anti-TB drugs are listed in Table 1 and reviewed in [34] . Rifampin resistance occurs in 95% of cases through nucleotide substitutions in an 81-bp core region of rpoB, the -subunit of DNA-dependent RNA polymerase [35,36] . INH resistance is more complicated and can be mediated by mutations in several

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Extensively drug-resistant TB: new strains, new challenges


genes, including katG (40­60% of the time), inhA, ahpC, oxyR, kasA, furA and ndh [34] . The mechanism of INH resistance is unknown in 10­15% of cases. Resistance determinants to many SLDs have also been elucidated. High-level FQ resistance occurs in more than 90% of cases via mutations in the quinolone resistance-determining region of the gyrA gene that encodes a DNA gyrase. Mutations in a similar gene, gyrB, can also confer FQ resistance. Low-level FQ resistance in the absence of gyrA/B mutations occurs rarely but has been observed [37,38] . Resistance to aminoglycosides, such as streptomycin, amikacin and kanamycin, occurs approximately 70% of the time in the rrs gene that encodes 16S ribosomal RNA [39] . Streptomycin resistance is also associated with mutations in the rpsL gene [40,41] and gidB [42] . A substitution at a single position in rrs generally confers high-level resistance to both amikacin and kanamycin [43] . However, mutations outside of this gene also cause aminoglycoside resistance without complete cross-resistance. Half of MDR isolates in Estonia that lacked rrs mutations were kanamycin resistant and amikacin sensitive [44] . Capreomycin resistance in M. tuberculosis is due to mutations in rrs [39] and tlyA [45] . Recently, the genomes of three related M. tuberculosis strains from Kwazulu-Natal (XDR, MDR and drug sensitive) have been sequenced using high-throughput DNA sequencing. These strains have a different genetic background from the F15/LAM4/KZN strain causing the majority of cases in South Africa. While the data are not yet published, they are publicly available on the website of the Broad Institute [201] . The genomes differ from one another through a surprisingly small number of single-nucleotide polymorphisms (SNPs). The XDR and drug-sensitive strain differ by 33 SNPs and one insertion/deletion. The XDR and MDR strains share a number of identical mutations conferring INH, streptomycin and ethambutol resistance. However, they differ by 22 SNPs and one insertion/deletion. Some mutations unique to the XDR strain are in genes known to mediate antibiotic resistance, including substitutions in the rpoB and gyrA genes and a deletion in the pncA gene. Other SNPs occur in genes without proven roles in drug resistance, such as mmpL13a that encodes a protein involved in fatty acid transport and cell wall synthesis. Additional SNPs in the XDR strain are in uncharacterized genes (Rv2000 and Rv3471c). It is possible that some SNPs are compensatory mutations that permit bacterial survival despite the loss of fitness that accompanies drug resistance.

Drug-susceptibility testing

In many resource-limited settings that lack laboratory equipment, infrastructure and personnel, culture and DST of M. tuberculosis are only performed when there is a treatment failure or suspicion of MDR-TB. It is estimated that in many countries, only 3% of new TB cases have access to DST [10] . In high-income nations that routinely perform M. tuberculosis cultures, time from initial receipt of specimen to first-line drug susceptibility results is approximately 1 month, due to the slow growth of M. tuberculosis. SLD-susceptibility tests are generally ordered when first-line drug resistance is identified and require

an additional 2­4 weeks. Programmatic obstacles can cause further delays in obtaining DST results. The long time between specimen submission and SLD-susceptibility results using conventional culture methods forces physicians to make empiric treatment choices, which may select for additional resistance, complicating treatment of XDR-TB patients [46,47] . Unlike testing of first-line TB drugs, susceptibility testing of SLDs has poor reproducibility and is not standardized throughout the world, even among national reference laboratories [48] . Critical concentrations used for testing SLDs vary greatly among laboratories [48,49] despite published recommendations [50] and validation of SLD-susceptibility testing by several groups [51­53] . There is also limited quality control of SLD testing, although efforts to expand proficiency testing of laboratories are underway [54,55] . Finally, the association between the in vitro efficacy of a SLD and the clinical outcome is not well established [50,51] . In the only multicenter study of SLD-susceptibility testing in laboratories using either liquid and solid-culture methods, significant discordance was noted in susceptibilities for cycloserine, ethionamide, capreomycin and, to a lesser extent, clofazimine and rifabutin [49] . Such discrepancies may arise if different methods are used during testing or if an isolate contains a mixed population or has borderline resistance to a drug. Molecular assays for rapid detection of genotypic drug resistance to first-line drugs have been developed and their value is becoming apparent. In theory, similar molecular strategies can be employed to design assays for rapid detection of genotypic resistance to SLDs [37] . The most common molecular strategies for detection of drug resistance in M. tuberculosis include SNP analysis, line-probe assays [56] and molecular beacons [57,58] . These assays can provide results within hours to days. Some are available as commercial kits but not all are approved by the US FDA. Commercial assays for rapid detection of diagnosis generally perform best when used on M. tuberculosis cultures or smearpositive clinical specimens, and are less sensitive when applied to smear-negative sputum or nonpulmonary specimens [59,60] . Since these assays have variable sensitivity, it is recommended that they be used together with phenotypic tests. Rifampin resistance is a useful surrogate marker for MDR-TB and presumably XDR-TB [59] . Expanded use of rapid assays that detect rifampin-resistance mutations is likely to improve case detection. Several line-probe assays that detect MDR-TB as well as INH or rifampin monoresistance have been used in settings with high TB and HIV prevalence and display good sensitivity and specificity [61,62] . Limitations of all molecular assays that detect genotypic drug resistance include failure to detect mutations located outside of the targeted loci, detection of silent mutations that might not cause phenotypic drug resistance and failure to detect subpopulations with emerging resistance in a mixed population of bacteria [57] . Therefore, confirmation with phenotypic testing is essential. Although molecular technologies have reduced the time required for laboratory diagnosis of M. tuberculosis, they have been costly and unavailable in many resource-limited settings. Other rapid and less expensive methods for M. tuberculosis



Banerjee, Schecter, Flood & Porco

detection and phenotypic DST that can be adapted for SLD susceptibility testing include microscopic observation drug susceptibility (MODS) and phage-based assays. MODS is a technique that visualizes, under a light microscope, characteristic cord formation of M. tuberculosis in liquid culture and allows for simultaneous DST and culture growth within approximately 7 days, almost 1 week faster than other techniques [63,64] . MODS sensitivity for detecting M. tuberculosis ranged from 92 to 98% in both smear-negative [65] and smear-positive respiratory samples [64,66] . Compared with standard culture methods, MODS was more sensitive for the detection of M. tuberculosis in pleural fluid or pleural biopsy specimens [67] but slightly less sensitive for the detection of M. tuberculosis in cerebrospinal fluid [68] . MODS also reliably detected MDR-TB [64,66] . The limitations of MODS are that it is technically more difficult than smear microscopy and cannot distinguish between M. tuberculosis and nontuberculous mycobacteria. Despite these problems, MODS is a promising new technique that has been used successfully in resource-limited areas and will soon be assessed in large clinical trials [59] . Phage-based assays are rapid, inexpensive, allow for both M. tuberculosis detection and phenotypic DST, and are commercially available. In these assays, M. tuberculosis cultures are infected with mycobacteriophages. Phage amplification (indicative of viable bacilli) is then detected as plaques on Mycobacterium smegmatis-containing plates [69] . Several meta-analyses concluded that phage-based assays display variable accuracy for the detection of M. tuberculosis but were highly sensitive and specific for the detection of rifampin resistance of M. tuberculosis cultures [70,71] . There are limited data on the performance of these assays directly on sputum samples [70] . Phage assays have been used successfully in resource-limited settings with a turnaround time of 48 h [72] . Tuberculosis programs treating MDR- and XDR-TB patients must expand their existing laboratory capacity. Accordingly, the WHO has committed to increasing laboratory capacity in national and supranational reference laboratories, and providing standardized guidelines for DST, especially for SLDs [73] . The WHO/StopTB has also called for accelerated access to rapid testing for rifampin resistance, in order to improve detection of MDR/XDR-TB cases [74] . In addition, improvements in quality control of DST among supranational and national reference laboratories are planned [3] .

Treatment principles

in vitro susceptibility; at least three of these should be new to the patient [77,78] . If an XDR-TB isolate remains susceptible to one of the bactericidal injectable agents, it must be used and continued for a minimum of 6 months following culture conversion and for 12 months for those patients with cavitation or delayed culture conversion. Treatment with at least three oral drugs should be continued for 24 months following culture conversion. To minimize acquired or amplified drug resistance, a single drug should never be added to a failing regimen and expert consultation with a TB clinician should be initiated as soon as the diagnosis is known or suspected. Patients with large cavities who are at a high risk for treatment failure should be considered for surgery if there is predominantly one-sided disease and the patient is a reasonable surgical candidate [79­85] . Early diagnosis and treatment with individualized regimens based on DST have led to high cure rates among MDR-TB patients, even in low- and middle-income nations [86­88] . Given the few drugs available to treat XDR-TB patients, these individuals may be infectious for long periods, fail treatment and need prolonged isolation, which is a challenge in all settings. Although hospital-based therapy has been the mainstay of MDR- and XDR-TB treatment, nosocomial transmission of drug-resistant TB has been well documented, most recently in the South African XDR-TB epidemic, and suggests that community-based treatment may be more effective in resource-limited settings that lack adequate isolation facilities. In addition, individualized care delivered in patients' homes or in nearby satellite clinics can reduce transportation costs and may improve adherence [11,59,86] . More research is needed on the feasibility and outcomes of community-based strategies for treatment of MDR- and XDR-TB.

Anti-TB drugs

Extensively drug-resistant TB is, by definition, resistant to both quinolones and injectable agents, the most potent second-line agents that form the cornerstone of MDR-TB treatment. As a result, treatment of XDR-TB is more difficult and less successful than that of MDR-TB. Effective drugs may not be available for XDR-TB patients who have had extensive prior TB treatment. However, many principles of the treatment of MDR-TB patients are applicable to XDR-TB patients [75,76] . To achieve adequate bacterial suppression and prevent selection of drug-resistant mutants, it is recommended that therapy include four to six drugs to which a M. tuberculosis isolate shows


Traditionally, anti-TB drugs are divided into first-, secondand third-line agents (Table 1) . The first-line drugs are INH, rifampin, ethambutol and pyrazinamide (PZA). The SLDs include the bactericidal injectable agents, FQs, cycloserine, ethionamide and para-aminosalicylic acid (PAS). Among the injectable agents are streptomycin (considered a first-line drug in some parts of the world), the aminoglycosides amikacin or kanamycin, and capreomycin, a polypeptide that has the same toxicity pattern and the same pharmacokinetics as the aminoglycosides. Among the FQs, levofloxacin and moxifloxacin are recommended over earlier FQs because they have greater efficacy against M. tuberculosis in vivo [89­93] . Third-line drugs include amoxicillin/clavulanate, imipenem, clarithromycin, linezolid and clofazimine. Several new agents including a diarylquinoline, two different nitroimidazoles, a pyrrole and a diamine, are in various stages of clinical development [94] . Suggestions for building a treatment regimen for XDR-TB are shown in Figure 2 , although there are limited clinical trial data to guide MDR- and XDR-TB treatment [95] . Most first-line agents are unlikely to be of use in the treatment of XDR-TB. However, if there is susceptibility to ethambutol or PZA, these drugs should be included in the regimen. A study from

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Extensively drug-resistant TB: new strains, new challenges


Peru showed statistically significant favorable outcomes when MDR-TB patients were treated with either ethambutol or PZA if the isolate was susceptible to the drug [86] . Because XDR-TB is resistant to FQs, it is generally necessary to use all remaining oral SLDs and any injectable agent to which the isolate is susceptible. Most experts in MDR-TB and XDR-TB recommend using at least four to six drugs, meaning linezolid, imipenem and/or other third-line drugs will be required. There is cross-resistance for several of the anti-TB agents. In cases of low-level INH resistance (from mutations in inhA), there is often cross-resistance to ethionamide. Amikacin and kanamycin frequently show cross-resistance to each other, although a recent study from Estonia found that approximately 50% of isolates resistant to kanamycin were not resistant to amikacin [44] . There is generally thought to be cross-resistance among the FQs ciprofloxacin, ofloxacin and levofloxacin, but there may not be full cross-resistance between earlier FQs and moxifloxacin [96] . Since ciprofloxacin has the least activity against M. tuberculosis

of all the quinolones, it is recommended to test for levofloxacin or moxifloxacin susceptibility in order to inform the treatment regimen, even if ciprofloxacin resistance has been reported. The drugs used for the treatment of XDR-TB are not as well tolerated as those used for the treatment of drug-sensitive disease. Regular patient monitoring for toxicity is necessary. Ethionamide, cycloserine, PAS, the quinolones, clofazimine and rifabutin all have gastrointestinal toxicity. Ethionamide, PZA, PAS and quinolones are also associated with hepatotoxicity. Hypothyroidism has been seen in patients taking ethionamide and/or PAS. Eighth nerve toxicity, manifested by vestibular toxicity and hearing loss is a relatively common side effect of the aminoglycosides and capreomycin. Renal insufficiency is also a complication of the injectable agents and needs close monitoring. Patients on cycloserine have been noted to have depression or frank delusional symptoms. Headache can be seen with cycloserine, ethionamide and the quinolones. Linezolid has been associated with peripheral neuropathy and myelosuppression as

STEP 1 Begin with any first-line agents to which the isolate is susceptible (PZA and EMB are commonly not susceptible) Add an injectable drug based on susceptibilities

Use any available First-line drugs PZA EMB

One of these (if susceptible) Injectable drugs Amikacin Capreomycin Streptomycin Kanamycin

STEP 2 With XDR-TB, often all three of these agents are necessary

Pick one or more of these Oral second-line drugs Cycloserine Ethionamide PAS

STEP 3 If there are not four to six drugs available in the above categories, consider third-line drugs in consultation with an XDR-TB expert

Consider use of these Third-line drugs Clofazimine Linezolid Amoxicillin/ clavulanate Imipenem Macrolides High-dose isoniazid

Figure 2. Building a treatment regimen for XDR-TB. EMB: Ethambutol; PAS: Para-aminosalicylic acid; PZA: Pyrazinamide; XDR: Extensively drug-resistant. Modified with permission from [108] .



Banerjee, Schecter, Flood & Porco

well as with visual loss. Individuals coinfected with HIV and TB may experience more adverse effects due to drug­drug interactions and overlapping toxicities of anti-TB and antiretroviral medications, paradoxical reactions due to immune reconstitution inflammatory syndrome and drug malabsorption due to advanced HIV disease [97] . Owing to the length and complexity of XDR-TB treatment, case management is critical. DOT should be provided throughout much, if not all, of the treatment course. DOT improves overall cure rates and results in a reduction in community prevalence of MDR-TB [98,99] . Case-management tools, such as drug-o-grams, bacteriology tables and flow charts for radiology or toxicity monitoring, are extremely helpful for monitoring treatment success or failure. Sputum smears and cultures should be collected monthly until cultures are consistently negative and then quarterly throughout treatment. Monitoring with chest x-ray, medical exam, symptom review and, if indicated, sputum collection for a minimum of 2 years following treatment is recommended by many experts. Therapeutic drug monitoring can be helpful in specific circumstances [100] , especially for cycloserine, which has variable absorption, and the injectable agents. There is little evidence available to inform the management of contacts of XDR-TB patients. The US CDC recommends using two drugs to which the isolate is susceptible in treating contacts of MDR-TB [101,102] . However, without the ability to use a quinolone or injectable agents, there are no available bactericidal options for treating latent infection with XDR-TB. One option is to follow infected contacts of XDR-TB for 2 years to detect early progression to active disease if it occurs. While contact investigation is not routinely performed in low-income, high-TB-incidence countries, a recent review found that the pooled yield of active household-contact investigations in low- and middle-income nations is 8.5% for active disease in children under 5 years of age. Targeting this highrisk group of young children for active contact investigations and treatment of latent TB infection could have a large impact on M. tuberculosis transmission [103] and is recommended by the International Union Against Tuberculosis and Lung Disease and the WHO [104] .


of XDR cases will continue to grow. Our ability to prevent and contain XDR-TB hinges on whether we can strengthen core TB program practices worldwide and implement novel diagnostics and therapeutics.

Expert commentary

Patients with XDR-TB have prolonged infectious periods, high mortality and limited treatment options. XDR-TB is curable but XDR-TB patients must be treated for years with drugs that are less potent and more toxic than common first- and secondline agents. In places with the laboratory capacity, DST should be performed on all M. tuberculosis isolates, using conventional methods as well as rapid molecular assays for the detection of INH and/or rifampin resistance. Isolates with resistance to first-line drugs should be tested for susceptibility to second-line agents. Expert consultation with a TB clinician is recommended for assistance with the complex management of MDR- and XDR-TB patients. In settings that lack adequate isolation facilities for XDR-TB patients, community-based treatment strategies may be necessary. Close collaboration between HIV and TB programs is essential, especially in areas where high HIV prevalence is contributing to the development of XDR-TB.

Five-year view

The alarming emergence of XDR-TB worldwide indicates that changes in current TB control practices are needed. The essential ingredients for increasing drug resistance continue to occur worldwide: inadequate treatment due to poor adherence, poor regimens or lack of timely susceptibility results, and transmission of drug-resistant strains. The implications for global communities are grave. If new TB drugs and rapid diagnostics are not developed and implemented shortly, XDR-TB will be an expanding fraction of TB cases. Core TB control measures include consistent use of DOT, isolation of infectious XDR patients, timely and effective treatment regimens and contact investigation [105­107] . If measures are not strengthened to prevent the development of resistance in drug-sensitive TB, the number


Extensively drug-resistant TB presents both a challenge and an opportunity for the TB community. New diagnostics and therapeutics for TB are critical to avert the global spread of XDR-TB. For the first time in decades, there are several new anti-TB drug candidates and candidate compounds under development or testing. Whether one or more of the compounds will prove effective in XDR-TB treatment is not yet clear. There is urgency to channel new anti-TB agents through the lengthy clinical development process as rapidly as possible and evaluate treatments for MDR- and XDR-TB in clinical trials. The CDC's Clinical Trial's Consortium and the US NIH are among the leading national agencies participating in TB-drug discovery and testing, and the Global Alliance for TB Drug Development has supported this initiative. Progress is expected in the next 5 years to ensure that SLD-resistance testing is standardized and rapid molecular assays for DST become accessible through reference and regional laboratories. Increasing HIV testing and treatment globally may have a significant effect on containing XDR-TB. More funding for research and development in M. tuberculosis diagnostics and treatment is essential in the next few years.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Expert Rev. Anti Infect. Ther. 6(5), (2008)

Extensively drug-resistant TB: new strains, new challenges


Key issues

· Extensively drug-resistant (XDR)-TB is found throughout the world. · XDR-TB is defined as TB that is resistant to at least isoniazid, rifampin, a fluoroquinolone and one of three injectable drugs (kanamycin, capreomycin and amikacin). · Multiple factors have contributed to the development of XDR-TB: the key ingredients have been overburdened public-health systems, inadequate laboratory capacity to culture and perform drug-susceptibility testing on TB isolates, widespread and poorly supervised use of second-line drugs, poor adherence to medications and high HIV prevalence. · XDR-TB patients have high mortality and longer infectious periods than patients with other forms of TB, although XDR-TB in some patients can be cured. · Current treatment options for XDR-TB are limited. · Rapid, standardized methods for diagnosis of drug-resistant TB are needed. · New drugs for TB treatment are needed to prevent XDR-TB from expanding. · Well-supported TB programs are crucial to prevent XDR-TB from developing in the first place.


Papers of special note have been highlighted as: · of interest ·· of considerable interest



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· Ritu Banerjee Division of Infectious Disease, Department of Pediatrics,University of California, San Francisco, 500 Parnassus Avenue, MU407E, San Francisco, CA 94143-0136, USA Tel.: +1 415 476 0136 Fax: +1 415 476 1343 [email protected] Gisela F Schecter California Department of Public Health (CDPH), Tuberculosis Control Branch, CA, USA Tel.: +1 510 620 3439 Fax: +1 510 620 3030 [email protected] Jennifer Flood California Department of Public Health (CDPH), Tuberculosis Control Branch, CA, USA Tel.: +1 510 620 3000 Fax: +1 510 620 3030 [email protected] Travis C Porco University of California, San Francisco, Francis I Proctor Foundation for Research in Ophthalmology, Department of Epidemiology and Biostatistics/Division of Preventive Medicine and Public Health, and Department of Ophthalmology, CA, USA Tel.: +1 415 476 4101 Fax: +1 415 4760527 [email protected]


















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